T cells play an important role in tumor regression in several animal tumor models. Clinical observations have demonstrated that the adoptive transfer of cultured cytotoxic T lymphocytes (CTLs) derived from tumor infiltrating T lymphocytes (TILs) supplemented with interleukin 2 (IL-2) result in tumor regression in 30-40% of patients with metastatic melanoma (Rosenberg et al., N. Engl. J. Med. 319:1676-1680, 1988; Rosenberg et al., JNCI 86:1159-1166, 1995). T cells also play a critical role in the in vivo rejection of melanoma as demonstrated by the presence of T cell infiltrates in regressing tumors after IL-2 based immunotherapy, as well as the association between the clinical response to TIL therapy and the accumulation of injected T cells in tumor sites (Kawakami et al. In: Devita VT, Hellman S, Rosenberg S A, eds. Principle and Practice of Oncology, Update. Philadelphia: Lippincott-Raven, 1997:1-20). In the past decade, immunotherapy and gene therapy utilizing T lymphocytes have emerged as new and promising methods for treating human disease, in particular human cancers. Therefore, identification of antigens recognized by these T cells could provide insight into tumor recognition by autologous T cells, as well as the development of new therapies for cancer patients.
Several studies have demonstrated that specific major histocompatibility complex (MHC)-class I restricted CTL responses are directed against a variety of tumor antigens (Hom et al., J. Immunother. 13:18-30, 1993; Van den Eynde, B. J. and P. van der Bruggen, Curr. Opin. Immunol. 9:684-693, 1997; Rosenberg, S. A., Immunity. 10:281-287, 1999). Based on their pattern of expression, tumor antigens can be grouped into four general categories: 1) tumor-specific shared antigens; 2) tumor-specific mutated antigens; 3) tumor-specific antigens, widely expressed in normal tissues; and 4) melanoma differentiation antigens (MDA).
The first group of tumor-specific shared antigens include cancer-testis antigens such as MAGE and NY-ESO-1. These antigens are expressed on a variety of tumors, including melanoma, but are not expressed in normal tissues except for the testis and placenta (Rosenberg, S. A., Immunity. 10:281-287, 1999; Takahashi et al., Cancer Res. 55:3478-3482, 1995; Chen et al., Proc. Natl. Acad. Sci. U.S.A. 94:1914-1918). The tumor-specific mutated antigens are those antigens which result from mutations and are therefore unique to each patient. These antigens include β-catenin (Robbins et al., J. Exp. Med. 183:1185-1192, 1996), CDK-4 (Wolfel et al., Science. 269:1281-1284, 1995), and MUM-1 (Coulie et al., Proc. Natl. Acad. Sci. U.S.A. 92:7976-7980, 1995). The third group of antigens, although widely expressed in a variety of normal tissues, is selectively expressed on tumors. These antigens include p15 (Robbins et al., J. Immunol. 154:5944-5950, 1995) and PRAME (Ikeda et al., Immunity. 6:199-208, 1997).
The fourth type of tumor antigen includes melanosomal proteins, such as melanoma differentiation antigens (MDA), including MART-1 (Kawakami et al., Proc. Nati. Acad. Sci. U.S.A. 91:3515-3519, 1994; Coulie et al., J. Exp. Med. 180:35-42, 1994), gp100 (Kawakami et al., Proc. Natl. Acad. Sci. U.S.A. 91:6458-6462), and tyrosinase (Brichard et al., J. EXP. Med. 178:489-495, 1993). Other MDAs which contain antigenic epitopes recognized by specific CTL in the context of HLA-A31 and HLA-A33 (Wang et al., J. Exp. Med. 184:2207-2216, 1996; Wang et al., J. Immunol. 160:890-897, 1998) include gp75/tyrosinase-related protein 1 (TRP1) Wang et al., J. Exp. Med. 181:799-804, 1995) and tyrosinase-related protein 2 (TRP2) (Wang et al., J. Exp. Med. 184:2207-2216, 1996).
TRP2 is a member of the tyrosinase-related gene family and exhibits approximately 40% amino acid homology to tyrosinase and TRP1. TRP2 is recognized by tumor-reactive CTLs in the mouse (Bloom et al., J. Exp. Med. 185:453-459, 1997) and human (Wang et al., J. Exp. Med. 184:2207-2216, 1996) and HLA-A2 restricted melanoma specific CTL epitopes have been identified in TRP2 using lymphocytes from repeated in vitro stimulation of donor peripheral blood mononuclear cells (PBMC; Parkhurst et al., Cancer Res. 58:4895-4901, 1998; Noppen et al., Int. J. Cancer. 87:241-246, 2000; Sun et al., Int. J. Cancer 87:399-404, 2000; Harada et al., Cancer Res. 61:1089-1094, 2001). Accordingly, the identification of genes encoding other members of the tyrosinase-related gene family and of peptides encoded by these genes, may be important in the treatment and detection of human melanoma and in its treatment and prevention.